1. Field of the Invention
The present invention provides heterocycle carboxamide derivatives. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
2. Technology Description
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causative agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
U.S. Pat. Nos. 5,753,666 and 5,891,878 and WO 97/04775 disclose specific 1-alkyl-substituted-quinolone-3-carboxamides that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
Commonly assigned WO 00/40561 discloses quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/40563 discloses specific quinolinecarboxamides as antiviral agents.
Commonly assigned WO 00/53610 discloses 4-Oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamides as antiviral agents.
Commonly assigned WO99/32450 discloses specific 4-hydroxyquinoline-3-carboxamides and hydrazides as antiviral agents.
U.S. Pat. No. 5,945,431 discloses specific naphthyridine heterocyclic compounds having antiviral activity that are useful in the therapy and prophylaxis of cytomegalovirus (CMV) infection in mammals.
WO99/10347 discloses specific substituted 4-oxo-naphthyridine-3-carboxamides as brain receptor ligands having potential use in the treatment of central nervous system diseases and/or disorders.
WO98/19673 discloses specific heterocyclic agents for the treatment of diseases caused by viruses.
JP08301849 discloses specific heterocyclic agents useful as tachykinin receptor antagonists. They are suggested for use in treatment of the following diseases: inflammation, allergic diseases, CNS disorders, digestive system disorders, urinary tract disorders, cardiovascular diseases immunopathy. The reference suggests that the inventive compounds can be used to treat herpes, but classifies herpes as either an inflammation or allergic reaction disease. The reference does not suggest that the compounds can be used to treat infectious diseases.
JP07033729 discloses specific N-cyano-Nxe2x80x2-substituted-arylcarboxyimidamide compounds exhibiting K+ channel opening effects and having hypotensive action and coronary vasodilating action.
WO 00/40562 discloses novel 2-oxoquinolines as selective peripheral cannabinoid receptor modulators).
WO 97/34894 dosloses Naphthyridine derivatives and their analogues inhibiting cytomegalovirus.
Despite the above teachings, there still exists a need in the art for novel compounds that demonstrate desirable antiviral activity.
In accordance with the present invention, novel compounds which demonstrate antiviral activity are provided. More specifically, the compounds are specific heterocycle carboxamide derivatives which are useful as antiviral agents, particularly against herpes viruses.
Even more specifically, the present invention provides a compound of formula I, 
wherein,
X is Cl, Br, F, CN or NO2;
G is
(a) C3-7alkyl which is partially unsaturated and is substituted by hydroxy, or
(b) C1-7alkyl substituted by NR1R2 or 4-tetrahydropyran;
R1 is C2-7alkyl substituted by hydroxy, C1-4alkoxy, aryl, or heteroaryl;
R2 is hydrogen or C1-7alkyl;
or R1 and R2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl or C1-7alkyl;
W is 
B is CR5 or nitrogen;
C is CR6 or nitrogen;
with the provisos that B and C cannot be both nitrogen;
R4 is H, halogen, or C1-4alkyl optionally substituted by one to three halogens;
R5 is
(a) H,
(b) halo,
(c) OR12,
(d) SR12,
(e) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12 SR12,or NR10R11,
(g) (Cxe2x95x90O)R9,
(h) S(O)mR9,
(i) (Cxe2x95x90O)OR2,
(j) NHSO2R9,
(k) nitro, or
(l) cyano;
R6 is
(a) H,
(b) halo,
(c) aryl,
(d) het, or
(e) R7;
R7 is
(a) OR12,
(b) SR12,
(c) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, aryl, halo,
C 3-8cycloalkyl optionally substituted by OR12, or het attached through a carbon atom,
(d) NR10R11,
(e) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12,or NR10R11,
(f) (Cxe2x95x90O)R9,
(g) S(O)mR9,
(h) (Cxe2x95x90O)OR2,
(i) NHSO2R9,
(j) nitro, or
(k) cyano;
R8 is
(a) H,
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(c) OR12, or
(d) SR12;
R9 is
(a) C1-7alkyl,
(b) NR10R11,
(c) aryl, or
(d) het, wherein said het is bound through a carbon atom;
R10 and R11 are independently
(a) H,
(b) aryl,
(c) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR2R2, CO2R2, het, aryl, cyano, or halo,
(d) C2-7alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR2R2, OR2, or SR2,
(e) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2, or
(f) R10 and R11 together with the nitrogen to which they are attached form a het;
R12 is
is (a) H,
(b) aryl,
(c) het
(d) C1-7alkyl optionally substituted by aryl, het, or halogen,
(e) C2-7alkyl substituted by OR2, SR2, or NR2R2, or
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2;
each m is independently 1 or 2;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR2R2, CO2R2, CF3, C1-6alkoxy, and C1-6 alkyl which maybe further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO2R2, CF3, C1-6alkoxy, oxo, oxime, and C1-6 alkyl which may be further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W and G;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof.
In particularly preferred embodiments, X is Cl and G is 4-morpholinylmethyl.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of the compound or salt.
Still another embodiment of the present invention provides a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes viral infection, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For this embodiment, in addition to the compounds encompassed by formula (I), G can also represent C1-7alkyl which is fully saturated and is substituted by hydroxy.
A further embodiment of the present invention comprises the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders caused by a viral infection, and particularly a herpes viral infection.
A final embodiment of the present invention comprises a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
An object of the present invention is to provide novel compounds having biological activity.
A further object of the present invention is to provide novel pharmaceutical compositions.
Still another object of the present invention is to provide a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes virus infection.
Another object of the present invention is to provide a method for inhibiting a viral DNA polymerase.
These, and other objects, will readily be apparent to those skilled in the art as reference is made to the detailed description of the preferred embodiment.